Although highly active antiretroviral therapy (HAART) has been successful in suppressing plasma HIV RNA levels in infected patients, it has not resulted in eradication of virus. It is now clear that prolonged, continuous HAART results in significant toxicities and adherence to drug regimens is difficult. In addition, the cost of HAART drugs is prohibitive for many countries and individuals. Therefore, we have studied the virologic and immunologic effects of intermittent versus continuous HAART in HIV-infected individuals in an attempt to reduce the total time an individual receives therapy while maintaining therapeutic efficacy. A reduction in the total amount of drugs individuals receive will decrease cost and may reduce toxicity while enhancing adherence. The studies include a randomized, controlled trial of long cycle intermittent HAART (1 month off HAART followed by 2 months on HAART for 22months) and a pilot study of short cycle intermittent HAART (7 days off HAART followed by 7 days on HAART for up to 24 months). Following 4-7 cycles of long cycle intermittent therapy, 19 of 22 patients had detectable plasma viremia after each of the 1 month off-drug periods. There was no significant difference in the mean plasma HIV RNA level between the 1st and the 4th cycles off drugs. However, all patients had a viral load of < 500 copies/ml following each of the 2 months on-drug periods; 70% of patients have plasma HIV RNA of < 50 copies/ml after the on-HAART periods. While there was a transient decrease in the mean CD4+ T cell count during each of the off-HAART periods, the mean CD4+ T cell count returns to the pre-interruption level following 4 weeks on-HAART with each cycle. Furthermore, 4 of 8 patients receiving efavirenz-based regimens developed new genotypic and phenotypic resistance to efavirenz following 4-6 cycles of long cycle intermittent HAART. Finally, although there was a significant reduction in serum lipid levels at 40 weeks of long cycle intermittent therapy (at the end of the 4th off-HAART period), by week 48, following 8 weeks on-HAART there was no significant reduction in these markers of toxicity compared to patients who received continuous therapy. In contrast, 8 of 8 individuals receiving short cycle intermittent HAART (7 days on-drug followed by 7 days off-HAART) maintained suppression of plasma HIV RNA for 96-104 weeks; all measurements were made after the off-HAART periods. In addition, there was no evidence for a significant increase in HIV replication during the off-HAART periods up to 52 weeks as determined by cell-associated HIV RNA, proviral DNA, replication-competent HIV in peripheral CD4+ T cells or lymph node HIV RNA. Finally, there was no evidence for the development of genotypic or phenotypic resistance to anti-retroviral agents for up to 26 cycles (52 weeks) of short cycle intermittent HAART. In regards to immunologic effects, there was no significant decrease in absolute CD4+ T cells or the percent of lymphocytes that are CD4+. In terms of markers of toxicity, there was a significant decrease in total serum cholesterol, LDL cholesterol and triglyceride levels following 12 months of intermittent therapy. These data demonstrate that it may be possible to maintain suppression of plasma HIV RNA, preserve CD4+ T cell counts and reduce parameters of toxicity utilizing short cycle intermittent HAART. However, long cycle intermittent HAART appears to be less favorable in terms of toxicity reduction. In addition, efavirenz, and other non-nucleoside reverese transcriptase inhibitors cannot be recommended for use in long cycle intermittent HAART strategies due to the increased risk of developing resistance to these agents. Intermittent HAART may be an important option for the treatment of HIV infection to reduce cost and possibly toxicty while potentially enhancing adherence.